Rachel LaRosa1, Clara Wruck2, Ashutosh Kumar3, ShaEssa Wright2, Melissa Yelton2, Ermal Aliu2, Dustin Paul3
1Neurology, Penn State Health Medical Center, 2Penn State Health Medical Center, 3Penn State Pediatric Neurology
Objective:
We report a case of a patient who presented with ID, ASD, abnormal gait, progressive feet deformity, joint hypermobility, Chiari malformation who was found to have a DYNC1H1 mutation and Klinefelter syndrome.
Background:
Mutations in the DYNC1H1 gene are associated with neurologic disorders including SMALED, CMT2O, and malformations in cortical development (MCD).
Design/Methods:
We report a 10-year-old male with ASD/ID, hypermobility and Chiari I malformation who presented with gait difficulties for 6 months, left foot turning inwards, paresthesia’s in bilateral feet, and one month of developmental regression. Neurologic exam shows cognitive delay, hypotonia, proximal > distal weakness in all extremities, hyporeflexia, and one-handed Gower sign. He has pes cavus, hammertoes, distal tapering of musculature in all extremities. Workup including MRI neuroaxis and electrodiagnostics were unrevealing. Whole exome sequencing revealed Klinefelter’s syndrome, and a heterozygous likely pathogenic variant c.4580 T>A p.(L1527Q) in DYNC1H1 gene (NM_001376.4).
Conclusions:
DYNC1H1 gene encodes cytoplasmic dynein heavy chain 1, part of the complex that plays a key role in axonal transport/neuronal migration. SMALED is characterized by muscle weakness and atrophy in the lower extremities, from congenital/early childhood loss of spinal cord motor neurons. CMT2O presents in early childhood with delayed motor milestones and distal-predominant weakness in lower more than upper extremities. Cortical brain malformations arise from defective neuronal proliferation/migration and are often associated with severe ID and epilepsy.
Over 100 pathogenic variants are reported in DYNC1H1 gene, only a handful in the linker domain (aa 1374–1867). While our patient has severe ID, brain imaging is normal, which has been reported previously in patients harboring mutations in this region. His likely pathologic mutation is most likely causing disease on the spectrum of SMALED to CMT2O with ID/ASD. Additionally, his hypermobility and Chiari malformation is likely due Klinefelter syndrome. Thus, we recommend broader genetic testing for children with atypical presentations.